We have established that the clinical course of experimental allergic encephalomyelitis (EAE) can be prevented using peptide specific immunotherapy. This therapy uses readily-synthesized, nonlinear, homogeneous peptide octamers, each monomer peptide tethered to a central lysine core. Our ongoing studies suggest that these peptide octamers are effective when administered prior to as well as when clinical disease is evident. During this period of our first award we demonstrated the peptide specific nature of this therapy and that this basic approach alters the course of disease in both rat and mouse models of EAE. Studies in progress strongly suggest that these peptide octamers also prevent the repeating episodes of clinical disease in a mouse model of relapsing EAE. This latter observation is noteworthy as the prevention of the relapse was achieved with octameric peptides containing monomers of the sensitizing encephalitogenic peptide. Octamers consisting of peptides identified by others as targets of pathogenic epitope spreading did not modify the relapse rate in the initial experiments that we have conducted. Our work to date has used primarily the SJL mouse strain to study the influence of our peptide-based immunotherapy and we have used encephalitogenic peptides of proteolipid protein (PLP) and myelin basic protein (MBP) to induce disease and to construct the octameric peptides. These octameric peptides also referred to as multiple antigenic peptides (MAPs), are not encephalitogenic when administered in soluble form. In our proposed studies contained in this application we will extend our studies to C57BL/6 as well as (SJL x C57BL/6)F1 mouse strains. The F1 studies will allow a more complete analysis of the impact of peptide specific MAP therapy in that the (SJL x C57BL/6)F1 mouse stain develops EAE following immunization with many different encephalitogenic peptides and also develops a relapsing/remitting form of EAE in response to encephalitogenic peptide immunization. These and others observations to be detailed in this application suggest to us that the influence of octameric peptides on well-defined models of neuroantigen specific autoimmune disease warrants further study, not only to provide insight into the mechanisms that lead to relapsing autoimmune disease but also for their very real translational value. PUBLIC HEALTH RELEVANCE: Project Narrative Autoimmune diseases such as Rheumatoid Arthritis and Multiple Sclerosis are chronic diseases that do not have successful treatment strategies. The treatments that do exist do not target the disease itself but are designed to alleviate the clinical impact of the disease. A desired approach to treat autoimmune disease is to target specifically and eliminate only the immune response that is responsible for the expression of the disease. The approach used in this application is the development of specific reagents that prevent the cells that are responsible for the autoimmune disease from developing. These reagents will also act to prevent the autoimmune cells, if they have developed, from reaching the target of the autoimmune disease and thus will act to prevent the continuation of the disease.